Oncoforum Urology: Prostate Cancer 2008 at a Glance

3.1. Diagnosis and staging 

Pelvic lymphadenectomy in patients with low-risk PCa undergoing radical prostatectomy is a controversial topic. During the AUA, Heidenreich et al [4] presented a study in 499 men with low-risk PCa who underwent radical prostatectomy and extended pelvic lymphadenectomy. A correlation between percentage of positive biopsies and the presence of lymph node metastases was calculated. In 5.8% of patients, lymph node metastases were identified. The percentage of positive biopsies had a significant impact on the presence and prediction of nodal disease. The risk of lymph node metastases increased significantly if ≥50% of the biopsy cores were involved with PCa (Fig. 1). Sensitivity and specificity were 91.4% and 82.1%, respectively.

View Large Image Download to PowerPoint

Fig. 1. The risk of nodal disease in men with ≥50% or <50% of the biopsy cores being positive for prostate cancer [4].

Prostate-specific antigen (PSA) progression is an accepted indicator of disease progression in hormone-sensitive and hormone-refractory PCa. Hussain et al [5] evaluated different definitions of PSA progression as predictors of overall survival, including consensus criteria using data from two phase 3 trials with adequate PSA and follow-up data. Patients from the S9346 trial received continuous androgen deprivation therapy and patients from the S9916 trial were treated with docetaxel or mitoxantrone plus prednisone. PSA progression was defined as an increase in PSA value of ≥25% over baseline or nadir with an absolute increase of ≥2 or 5 ng/ml. Survival analysis revealed PSA progression observed with both PSA thresholds as a strong predictor of overall survival in metastatic hormone-sensitive and hormone-refractory PCa patients irrespective of the initial PSA (Fig. 2).

View Large Image Download to PowerPoint

Fig. 2. Use of prostate-specific antigen (PSA) progression to predict overall survival in patients with metastatic prostate cancer treated with continuous androgen deprivation therapy (phase 3 S9346 trial) and docetaxel or mitoxantrone plus prednisone (phase 3 S9916 trial) [5].

3.2. Localised prostate cancer 

Positive apical surgical margins have not traditionally been treated as other positive surgical margins after radical prostatectomy. Lassoff et al [6] examined the margin status in 1663 clinically localised (cT1/cT2) PCa patients who underwent surgery between 1988 and 2003 to determine if there were any differences in outcomes. Patients were subdivided into nonapical positive surgical margin (SM+), apical positive surgical margin (AM+), and negative surgical margin (SM−): 16% of patients had SM+, 11% of patients had AM+, and 73% of patients had SM−. At a median follow-up period of 6.8 yr, patients with AM+ seem to behave similarly to patients with SM+ with respect to overall survival, biochemical recurrence-free survival, and clinical recurrence-free survival. Therefore, these patients may warrant a similar treatment approach following surgery. Quality of life after curative treatment of localised PCa—in particular, satisfaction of patients with treatment choice and treatment results—is an important end point. Between 2003 and 2004, 1083 PCa patients underwent radical prostatectomy in a German institution [7]. Complete follow-up data were available for 779 patients. Three questionnaires were used to evaluate quality of life, potency, and continence. In addition, the degree of information that patients received on PCa and their treatment before surgery was assessed. Overall, satisfaction with treatment was very good in 84% of the patients and good in 14% of the patients. In uni- and multivariate analyses, a high level of preoperative information about disease and treatment (p<0.001), postoperative potency (p<0.001), and postoperative continence (p<0.001) were significantly associated with good satisfaction with treatment. Aspects of cancer control (ie, cancer stage and surgical margin) had no significant impact on treatment satisfaction.

Active surveillance has emerged as an alternative to radical therapy for patients with small, localised, well-differentiated PCa, the incidence of which is increasing due to screening. A retrospective study presented at the EAU annual meeting validated the currently used criteria for eligibility for active surveillance [8]. Data from 616 men who were diagnosed with PCa between 1994 and 2007 in four centres of the European Randomised Study of Screening for Prostate Cancer (ERSPC) were combined. All patients fit the Prostate Cancer Research International Active Surveillance (PRIAS) criteria for active surveillance (PSA ≤10.0 ng/ml, PSA density<0.2 ng/ml per millilitre, category T1c/T2, Gleason score ≤3 + 3=6, and ≤2 positive biopsy cores) and were managed expectantly. Median follow-up was 3.91 yr. PSA characteristics and disease-specific and overall survival were studied (Table 1). Another multicentre retrospective study investigated the safety and risk of systemic progression in 262 patients with localised and low-risk PCa electing active surveillance between 1991 and 2007 [9]. At a median follow-up of 29.7 mo, 16.4% of patients subsequently underwent primary therapy. The 1-, 2- and 5-yr actuarial probabilities of remaining on active surveillance were 95%, 91%, and 75%, respectively. Twenty-six patients (9.9%) underwent radical prostatectomy. One patient (0.4%) on active surveillance had a PSA rise from 6 to 24 ng/ml over a 6-mo period and developed skeletal metastases.

Table 1. Outcomes of men with screen-detected prostate cancer eligible for active surveillance who were managed expectantly [8]

	Mean PSA at diagnosis (ng/ml)	4.3
	Death (% of patients)	9
	Disease-specific death (% of patients)	0
	10-yr overall survival (%)	77
	10-yr disease-specific survival (%)	100

PSA=prostate-specific antigen.

With regard to radiotherapy, a multicentre, randomised, controlled Groupe d’Etude des Tumeurs Uro-Génitales (GETUG) 06 study was conducted in 306 patients with intermediate-risk PCa to compare clinical outcomes after 70 Gy (n=153) or 80 Gy (n=153) dose radiotherapy [10]. The median follow-up was 59 mo. Using the Phoenix relapse definition (nadir plus 2 ng/ml), biological relapses were 31.0% and 23.5% for the 70 Gy group and 80 Gy group, respectively. There were no statistically significant differences between the two arms for rectal toxicity and quality of life at 5-yr follow-up. Therefore, 80Gy did not seem to provide a better outcome than 70Gy radiotherapy in patients with intermediate risk PCa at a short follow-up.

Conflicting results on the risk of developing secondary malignancies following treatment for PCa have been reported. Several studies presented at the ASTRO annual meeting investigated a putative increased secondary cancer risk subsequent to PCa treatment. An analysis of the Surveillance, Epidemiology, and End Results (SEER) registry demonstrated that the incidence of bladder cancer seems to remain low but slightly increased after curative treatment for PCa [11]. In multivariate analysis, increasing age, surgery, and irradiation were highly significant predictors of developing bladder cancer. In contrast, Tward et al [12] reported that men from a large SEER database with primary PCa undergoing radical prostatectomy, external beam combined with brachytherapy or brachytherapy alone had no statistically elevated risk of developing any overall or particular “in-field” malignancy. Another retrospective multicentre study demonstrated that external beam radiotherapy was predisposed to a 3.0-fold higher rate of cystectomy for bladder cancer (p=0.04), a 1.8-fold higher rate of lung cancer surgery (p=0.02), and a 1.7-fold higher rate of rectal cancer (p=0.02) by multivariate analyses [13]. Overall, we do not have apparent data yet on the risk of developing secondary malignancies after PCa treatment. Confounding factors such as smoking, which have never been studied, should be taken into consideration.

3.3. Locally advanced prostate cancer 

Men with pT3 PCa are considered to have a higher risk of recurrence than those with organ-confined disease. The randomised phase 3 Southwest Oncology Group (SWOG) 8794 trial enrolled 425 men with pT3 PCa between 1988 and 1997 and addressed the benefit of adjuvant radiotherapy to surgery [14]. At a median follow-up of 10 yr, adjuvant radiotherapy to radical prostatectomy resulted in an increased biochemical control and a decreased local failure over surgery alone. Although there was a trend towards improvement, the impact of adjuvant radiotherapy on overall and metastatic-free survival was not statistically significantly improved. At the ASTRO annual meeting, updated results were presented. Adjuvant radiotherapy significantly improved 15-yr metastasis-free survival (Fig. 3) [15]. According to a recent publication, overall survival also was significantly improved with adjuvant radiation (p=0.023) [16]. With regard to patients with lymph node-positive PCa treated with radical prostatectomy and pelvic lymph node dissection, only a few studies have assessed factors predicting long-term survival. Briganti et al [17] developed and internally validated a nomogram predicting cancer-specific survival in node-positive PCa patients treated with a multimodal approach. By multivariate analysis, number of positive nodes, pathologic Gleason score, surgical margin status, and adjuvant radiotherapy were significant predictors of cancer-specific survival (all p≤0.01). A nomogram based on preoperative PSA, pathologic stage, Gleason score, surgical margin status, number of positive nodes, and adjuvant radiotherapy demonstrated an accuracy of 72.7%.

View Large Image Download to PowerPoint

Fig. 3. Benefit of adjuvant radiotherapy to radical prostatectomy among men with pT3 prostate cancer enrolled in the Southwest Oncology Group (SWOG) 8794 trial [15].

3.4. Hormone-refractory prostate cancer 

A proportion of castration-resistant PCa overexpresses androgen synthetic enzymes and remains dependent on androgens for growth. Abiraterone acetate is an inhibitor of 17 α-hydroxylase C17,20-lyase (CYP17), a dual enzyme responsible for androgen synthesis. The mechanism of action of abiraterone is similar to ketoconazole, which inhibits multiple adrenal CYP enzymes, including CYP17. Several phase 1/2 studies presented at the ASCO annual meeting investigated the effect of abiraterone acetate on PSA decline [18], [19], [20]. In addition, the impact of prior ketoconazole therapy on abiraterone response was examined [19]. Abiraterone acetate appears to be well tolerated and effective in patients with castration-resistant PCa, even in patients experiencing disease progression on ketoconazole (Table 2) [18], [19], [20].

Table 2. Effect of abiraterone acetate on prostate-specific antigen (PSA) levels in patients with castration-resistant prostate cancer

		Logothetis et al [18] (n=17)	Ryan et al [19] (n=30)	Danila et al [20] (n=38)
	Treatment (wk)	8	12	12
	PSA decline ≥50% (% of patients)	41.1	43.0	40.0